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The findings of Du et al. provide an important advance in understanding the mitochondrial amyloid β (Aβ) toxicity in Alzheimer disease (AD) pathogenesis. Their findings suggest that mitochondrial Aβ interacts with the mitochondrial matrix protein, cyclophilin D (CypD), to induce free radical production, increase neuronal oxidative stress, and damage neurons. In addition, they also found that CypD-deficient cortical neuronal mitochondria are resistant to Aβ and Ca2+ induced mitochondrial swelling. Further, CypD-deficient cortical mitochondria have reduced free radical production, and protect neurons from Aβ- and oxidative stress-induced cell death. These important findings further support the mitochondrial oxidative stress hypothesis of AD, and may have some important implications for mitochondrial targeted antioxidant therapeutics in AD.

Mitochondrial oxidative damage is an early event observed in AD patients and transgenic mouse models of AD (Reddy and Beal, 2008). Further, mitochondrial oxidative damage has been found in peripheral cells (platelets and fibroblasts) from AD patients. Recently, we (Manczak et al., 2006) and others (Crouch et al., 2005; Caspersen et al., 2005; Devi et al., 2006) focused on Aβ and mitochondria and demonstrated the presence of Aβ monomers and oligomers in the mitochondrial membranes. Our digitonin fractionation analysis of isolated mitochondria from APP-transgenic mice revealed Aβ in outer and inner mitochondrial membranes and the mitochondrial matrix. We also showed that mitochondrial Aβ decreases cytochrome oxidase activity, increases free radical production and carbonyl proteins, and damages AD neurons (Manczak et al., 2006). Recently, Hansson Petersen and colleagues reported that Aβ can be transported into mitochondria via the translocase of the mitochondrial outer membrane machinery, and that transported Aβ accumulates on the cristae of mitochondrial inner membrane (Hansson Petersen et al., 2008). These recent discoveries suggest that mitochondrial dysfunction and Aβ play a large role in AD development and progression.

However, it is unclear if CypD has a direct role in AD pathogenesis or whether its interaction with soluble Aβ just facilitates the formation of mitochondrial permeability transition pore leading to mitochondrial damage. We need further research to answer these possibilities. It is clear that CypD expression increases with age in APP mice and AD postmortem brains (Reddy et al., unpublished results), and this age-dependent, increased CypD expression may contribute to the opening of mitochondrial permeability transition pore in addition to Aβ interactions with several mitochondrial proteins.

The paper is very interesting. Importantly, this study supports our data regarding the localization of Aβ to the mitochondrial inner membrane (Petersen Hansson et al., 2008). They convincingly show that Aβ interacts with cyclophilin D, which is believed to be part of the mitochondrial permeability transition pore. The data suggest a mechanism for how Aβ exerts its toxicity once imported into mitochondria via the TOM import machinery.